Introduction to Etanercept (Enbrel)
Etanercept is a ‘biologic’ drug. Biologic drugs are designed to target aspects of the immune system, which behaves abnormally in RA. Etanercept was specially designed to neutralise tumour necrosis factor alpha (TNFα), an important molecule produced during inflammation, and is sometimes described as an ‘anti-TNFα’ drug. It is given by an injection under the skin, once a week. In the past, it was given twice a week, in smaller doses.
Etanercept has now been used to treat RA for more than ten years. In 1997, Moreland reported in the New England Journal of Medicine that etanercept suppressed disease activity and relieved symptoms in patients with RA who had not responded to other conventional disease modifying drugs (DMARDs). Since then, numerous studies in the USA, Europe and other countries have confirmed that etanercept is very effective in RA – both in long-term disease and also in newly diagnosed early RA. Two good examples of major clinical trials studying the use of etanercept in RA are the TEMPO and COMET studies.
The TEMPO Study, reported in 2004 in the Lancet, was a large, well-designed, double-blind international study (a double-blind study means that neither the patients nor the prescribers were aware of which patients were in the control group and which were in the experimental group). Patients with RA who had not responded to a previous DMARD were started on either methotrexate alone, etanercept alone, or a combination of the two. The study used the American Rheumatism Association (ACR) criteria; the gold standard for categorizing this condition. Under this criteria, patients are assessed for an improvement of their symptoms by percentage, with ACR 20 being a 20% improvement, ACR 50 a 50% improvement and ACR 70 a 70% improvement of symptoms.
After a period of a year, it was clear that the combination of etanercept and methotrexate provided much better results - with almost 50% of people achieving an ACR 70 response and approximately 40% going into remission (i.e. having no painful or swollen joints and no flare ups of their RA) - such results were previously unheard of. During subsequent years of follow-up, these excellent responses were found to persist, without new side-effects developing. It was even more striking to observe that that the combination of etanercept and methotrexate appeared to stop worsening of x-ray changes in the joints – an effect that again persisted over the further years of study.
The first year data from the COMET study was reported in the Lancet in 2008. This compared standard treatment of methotrexate with the combination of etanercept and methotrexate in patients with early RA. Patients taking the combination of etanercept and methotrexate fared better than those on methotrexate alone – with as many as 50% going into full remission (and many more enjoying low disease activity). In addition, far fewer patients taking the combination of etanercept and methotrexate had to stop work during the year, compared to those on methotrexate alone.
Side-effects of Etanercept
Most people tolerate etanercept well. One of the most common side-effects of etanercept is an injection site reaction, but this becomes less common after the first month of treatment. However, as with the other TNFα inhibitor drugs, etanercept suppresses an important molecule that is produced in inflammation – whether due to infection or RA. This suppression of TNFα is responsible for the beneficial effects in reducing inflammation in RA, but also explains the more serious potential side-effects: an increased susceptibility to infection. Trivial infections may persist a little longer than normal in some people but, more importantly, more serious infections such as pneumonias and septicaemias (blood poisoning) may develop in others. The hundreds of patients receiving etanercept in clinical trials did not get any more serious infections than the patients taking methotrexate. However, experience in real-life, outside clinical trials, suggests that etanercept (like all of the other anti TNFα inhibitors) can increase the risk of serious infection by roughly 20%. It is important for patients taking etanercept to contact their doctor, rheumatologist or rheumatology specialist nurse if they feel that they are starting with an infection and receive antibiotics if necessary.
Whilst the risk of extra infection can be reduced by keeping up to date with vaccinations, it is important to know that not all vaccinations can be given when on this drug. Inactivated (killed) vaccines such as influenza are fine (and indeed very important) to have. Live attenuated vaccines (such as yellow fever), should be avoided as they may be unsafe. Patients on etanercept should inform their doctor that they are taking this drug before receiving any vaccine.
If you are taking etanercept and have come into contact with someone having chickenpox or shingles, you may be more likely to contract this condition than others would be. If you develop any symptoms it will be important to contact your doctor to have a course of anti viral drugs starting as soon as possible.
As well as being important in fighting infection, TNFα is potentially important in the body’s defence against cancer. It is theoretically possible, therefore, that suppressing this chemical may result in a higher chance of developing cancer. However, over the many years of experience with etanercept and the other anti-TNFα drugs, there have been isolated reports, but not firm and consistent evidence for a greater incidence of cancer developing than would have been expected if patients were not taking this drug. This is something that registries, such as The British Society of Rheumatology Biologics Register (BSRBR) will help answer (The BSRBR register tracks the progress of patients with severe rheumatoid arthritis (RA), who are receiving biologic agents, monitoring the safety and effectiveness of these treatments over a long-term period). At present, whilst there is no strong evidence to suggest an increased risk of cancers or other tumours, rheumatologists are advised not to start this drug in patients who are currently being treated for, or have recently had, a cancer.
The UK National Institute for Health and Clinical Excellence (NICE) has approved the use of etanercept as a cost-effective therapy for RA (after failure or intolerance to two DMARDs including methotrexate and high disease activity), juvenile idiopathic arthritis, ankylosing spondylitis, psoriasis and psoriatic arthritis. Many other countries around the world allow etanercept and other TNFα inhibitors to be used in patients with less severe RA and also earlier in the course of the disease.
Advice on travelling when taking etanercept
Before travelling abroad, it is very important to keep up to date with vaccinations – but remember to avoid live vaccines. Etanercept can now be stored at room temperature (up to 25°C) for a single period of up to 4 weeks, making it much easier to carry when travelling by air. However, it should not be refrigerated after this. The company who provide your medication may be able to offer you more information on travelling with etanercept.
If you have an operation planned, you should contact your rheumatologist who can advise you as to when to stop your etanercept prior to the operation. This can depend upon the type of operation planned. If you need an emergency operation and are taking etanercept, you should not worry, as the risk of not having the operation is likely to be far worse than a small risk of infection that may occur when on etanercept. The most important thing is to tell your surgeon about your medication.
It is not generally a problem to drink alcohol whilst on etanercept. However, some people taking this drug will also be on other medications, such as methotrexate, in which case the consumption of alcohol should be limited.
Pregnancy and breastfeeding:
Reports of unexpected pregnancies while on etanercept suggest the outcome of the pregnancy for both mother and baby is just the same as when this drug has not been taken. However, no one really knows the risk of etanercept to an unborn baby. If you are thinking of becoming pregnant in the near future or if you are not using contraception, you should discuss the most appropriate treatment options with your rheumatology team. The drug manufacturer does not recommend taking etanercept whilst breastfeeding and suggests that breastfeeding should only take place after being off the drug for at least 6 months.
NRAS booklet: Biologics, The story so far
NRAS article: Anti TNF Treatment
References available on request
Professor Robert J Moots BSc (hons) MBBS (hons) PhD FRCP, Professor of Rheumatology, University Hospital Aintree, University of Liverpool
Original article: 24/08/2004
Next review due: 09/09/2016